Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis

Knox, Hayley L.; Sinner, Erica K.; Townsend, Craig A.; Boal, Amie K.; Booker, Squire J.

doi:10.1038/s41586-021-04392-4

Cited by 47 publications

(65 citation statements)

References 54 publications

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“…For the S N 2 and S N 2‐like methylation reaction catalysed by MTs three catalytic mechanisms have been described. In addition a radical‐based SAM mechanism exists [9a,b,44] as indicated above (see section 2): a recent review covers this topic and it will therefore not be discussed here [9b,33b–e] …”

Section: Catalytic Mechanisms Of Sam‐dependent Mtsmentioning

confidence: 99%

Methyltransferases: Functions and Applications

et al. 2022

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In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs, and approaches to utilise SAM as a cofactor in synthesis are introduced with different supply and regeneration approaches evaluated. The use of SAM analogues are also described. Finally O-, N-, C-and S-MTs, their synthetic applications and potential for compound diversification is given.

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Section: Catalytic Mechanisms Of Sam‐dependent Mtsmentioning

confidence: 99%

Methyltransferases: Functions and Applications

et al. 2022

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“…These enzymes share 79% sequence identity and a common substrate, (2R,3R,5R)-pantetheinylated carbapenam (PCPM, 1). However, TokK and ThnK differ in the number of methylations they catalyze in the biosyntheses of asparenomycin (6) and thienamycin (5), respectively (Scheme 1). [1][2][3][4] The differences in the kinetic behavior of these two enzymes have been previously discussed, 1 and the recent structural characterization of TokK greatly improved our mechanistic understanding of Cbl-dependent rSAM methyl transfer.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] The differences in the kinetic behavior of these two enzymes have been previously discussed, 1 and the recent structural characterization of TokK greatly improved our mechanistic understanding of Cbl-dependent rSAM methyl transfer. 5 Despite these advances, however, the stereochemical course of methylation by TokK could not be determined directly from the structure.…”

Section: Introductionmentioning

confidence: 99%

Stereochemical course of cobalamin-dependent radical SAM methylation by TokK and ThnK

2022

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“…Consecutive methyl transfer processes have been observed for several class B RSMs such as PoyC, [ 54 ] CysS, [ 55‐56 ] and ThnK. [ 57‐59 ] In the reaction of the latter two enzymes, a second (or even third) methyl group can be installed on the nascent methyl group resulting from the first methyl transfer process. Because TsrM does not produce dAdo radical and appears unable to methylate a sp 3 carbon, we reasoned that 1 is not 2‐ethyltryptophan (2‐EtTrp) as a result of methyl transfer to the newly installed 2‐methyl group.…”

Section: Resultsmentioning

confidence: 99%

Consecutive Methylation Catalyzed by TsrM, an Atypical Class B Radical SAM Methylase

Ding

Zhang

2022

Chin. J. Chem.

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Comprehensive Summary TsrM is a cobalamin‐dependent radical S‐adenosylmethionine (SAM) methyltransferase belonging to the Class B radical SAM methylase (RSM) family. This enzyme catalyzes the C‐2 methylation of L‐tryptophan to produce 2‐methyltrytophan (2‐MeTrp), an intermediate involved in the biosynthesis of thiostrepton A. In this work, we report characterization of an unexpected activity of TsrM, which carries out an additional methylation reaction on the product 2‐MeTrp. A series of isotopic labeling studies and assays with different Trp analogs revealed that TsrM is able to transfer a methyl group from SAM to the C4 of 2‐MeTrp to produce 2,4‐dimethyltryptophan. These results reveal the intriguing substrate specificity of TsrM, further expanding the reaction promiscuity of the radical SAM superfamily enzymes.

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Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis

Cited by 47 publications

References 54 publications

Methyltransferases: Functions and Applications

Methyltransferases: Functions and Applications

Stereochemical course of cobalamin-dependent radical SAM methylation by TokK and ThnK

Consecutive Methylation Catalyzed by TsrM, an Atypical Class B Radical SAM Methylase

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